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Am J Physiol Heart Circ Physiol (September 5, 2002). doi:10.1152/ajpheart.00421.2002
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Articles in PresS, published online ahead of print September 5, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00421.2002
Submitted on May 20, 2002
Accepted on August 29, 2002

Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-RasA and MAPK1/2 signaling

James D. Stockand1* and J. Gary Meszaros2

1 Department of Physiology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
2 Department of Physiology, Northeastern Ohio Universities College of Medicine, Rootstown, OH, USA

* To whom correspondence should be addressed. E-mail: Stockand{at}uthscsa.edu.

Aldosterone plays a pathologic role in cardiac fibrosis by directly affecting cardiac fibroblasts. Understanding of the cellular mechanisms of aldosterone action in cardiac fibroblasts, however, is rudimentary. One possibility is that aldosterone promotes proliferation of cardiac fibroblasts by activating specific cellular signaling cascades. The current study tests whether aldosterone stimulates proliferation of isolated adult rat cardiac myofibroblasts (RCF) by activating Kirsten Ras (Ki-RasA) and its effector MAPK1/2 cascade. Aldosterone (10 nM) significantly increased RCF proliferation. This action was sensitive to the mineralocorticoid receptor (MR) antagonist, spironolactone. Expression of MR in RCF and whole rat heart was confirmed by immunoblotting. Aldosterone significantly increased absolute and active (GTP-bound) Ki-RasA levels in RCF. Aldosterone, in addition, significantly increased phospho-c-Raf and phospho-MAPK1/2. The effects of aldosterone on Ki-RasA and phospho-c-Raf proteins were inhibited by spironolactone but not RU486, suggesting that aldosterone acts via MR. Inhibitors of MEK1/2 and c-Raf prevented aldosterone-induced activation of MAPK1/2 and proliferation. These results show that aldosterone directly increases RCF proliferation through MR-dependent activation of Ki-RasA and its effector MAPK1/2 cascade. Activation of cardiac fibroblasts through such as cascade may play a role in the pathological actions exerted by aldosterone on the heart.




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